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Clinical study on autoimmune hepatitis in adults: In a prospective, double-blind, randomised, multicentre trial, 207 patients with active autoimmune hepatitis (AIH) without cirrhosis were treated with initial daily doses of 3mg budesonide three times daily (n=102) for up to 6 months or 40 mg/day prednisone (tapered to 10mg/ day, n=105). Upon biochemical remission, the budesonide dose was reduced to 3 mg twice daily (6mg/day). Patients also received 1-2 mg/kg/day azathioprine throughout the study. The composite primary endpoint was complete biochemical remission (i.e. normal serum levels of aspartate- and alanine-aminotransferase) without occurrence of predefined steroid-specific side effects at 6 months. This primary endpoint was achieved in 47% of the patients in the budesonide group and 18% of the patients in the prednisone group (p<0.001).
Regarding secondary efficacy variables, at 6 months, complete biochemical remission occurred in 60% and 39% of the patients in the budesonide group and in the prednisone group, respectively (p=0.001). 72% and 47% of the patients in the budesonide group and in the prednisone group, respectively, did not develop steroid-specific side effects (p<0.001). The mean decrease in IgG and γ-globulin concentrations and the decrease in the rates of patients with elevated IgG and γ-globulin concentrations did not show any differences between treatment groups.
An open-label follow-up treatment of additional 6 months was offered to all patients after the controlled, double-blind phase. A total of 176 patients proceeded to this open-label phase and received budesonide 3 mg twice daily in combination with 1-2 mg/kg/day azathioprine. Rates of patients with biochemical remission and rates of patients with complete response (not statistically significant) were still higher in the original budesonide group (complete response rate 60% and biochemical remission 68% at the end of the open-label phase) than in the original prednisone group (complete response rate 49% and biochemical remission 51% at the end of the open-label phase).
Clinical study in patients with Crohn's disease: In a randomized, double-blind, double-dummy trial in patients with mild to moderate Crohn's disease (200 < CDAI < 400) affecting the terminal ileum and/or the ascending colon the efficacy of 9 mg budesonide in a single daily dose (9 mg OD) was compared to the treatment with 3 mg budesonide given three times daily (3 mg TID).
The primary efficacy endpoint was the proportion of patients in remission (CDAI<150) at week 8. A total of 471 patients were included in the study (full analysis set, FAS), 439 patients were in the per protocol (PP) analysis set. There were no relevant differences in the baseline characteristics in both treatment groups. At the confirmatory analysis, 71.3% of the patients were in remission in the 9 mg OD group and 75.1% in the 3 mg TID group (PP) (p: 0.01975) demonstrating the non-inferiority of 9 mg budesonide OD to 3 mg budesonide TID.
No drug-related serious adverse events were reported.
Clinical study on autoimmune hepatitis in paediatric patients: The safety and efficacy of budesonide in 46 paediatric patients (11 males and 35 females) aged from 9 to 18 years were studied as a subset of patients of the previously mentioned clinical study. 19 paediatric patients were treated with budesonide and 27 received the active control (prednisone) for induction of remission with a daily dose of 9 mg budesonide. After 6 months in the study, 42 paediatric patients continued for a further 6 months on open-label, follow-up treatment with budesonide.
The rate of complete responders (defined as biochemical response, i.e. normalisation of liver transaminases [AST and ALT] and lack of steroid-specific side effects) in patients aged ≤ 18 years was considerably lower compared to adult patients. There was no significant difference seen between the treatment groups. After follow-up treatment with budesonide for a further 6 months, the rate of paediatric patients with complete response was still slightly lower compared to adult patients but the difference between the age groups was much smaller. There was no significant difference in the rate of complete responders between those originally treated with prednisone and those treated continuously with budesonide. Therefore, the safety and efficacy of Budenofalk in children and adolescents have not been established, and no dosage recommendations can be given.
Pharmacokinetics: Absorption: Due to the special gastro-resistant film-coating of the pellets contained in Budenofalk 3 mg hard capsules, absorption occurs after a lag phase of 2-3 hours. In healthy volunteers as well as in patients with Crohn's disease, mean peak plasma levels of approx. 1-2 ng/ml budesonide were measured at about 5 hours after a dose of 1 capsule of Budenofalk 3 mg before meals. Maximal release occurs in the terminal ileum and caecum, the main areas of inflammation in Crohn's disease.
Release of budesonide from Budenofalk 3 mg in ileostomy patients is comparable to that in healthy subjects or patients with Crohn's disease and about 30-40% of the released budesonide was found in the ileostomy bag. This shows that a considerable amount of budesonide from Budenofalk 3 mg will be transported normally into the colon.
Concomitant intake of food can delay gastrointestinal passage by approx. 2-3 hours. The lag phase in such cases is about 4-6 hours, but this does not change the rate of absorption.
Distribution: Budesonide has a high volume of distribution (approx. 3 l/kg). Plasma protein binding averages between 85 and 90%.
Biotransformation: Budesonide undergoes extensive biotransformation in the liver (approx. 90%) to metabolites with low glucocorticoid activity. The glucocorticosteroid activity of the main metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide.
Elimination: The average elimination half-life is about 3-4 hours. Oral bioavailability both in healthy volunteers and in fasting patients with Crohn's disease is approx. 9-13%. Budesonide clearance is approx. 10-15 l/min.
Specific patient groups (patients with hepatic dysfunction): Depending on the type and severity of the liver disease, the metabolism of budesonide via CYP3A in these patients can be decreased. As has been shown for patients with autoimmune hepatitis, the systemic availability of budesonide in patients with hepatic dysfunction may be increased. As soon as liver function improves, the metabolism of budesonide normalises as well. The systemic availability of budesonide is significantly higher in patients with late stage primary biliary cirrhosis (PBC Stage IV) than in those in the early stages of the disease (PBC Stage I/II); the areas under the plasma concentration-time curves were on average three times higher after repeated doses of 3 x 3 mg budesonide daily.
Toxicology: Preclinical safety data: Acute toxicity: Acute toxicity of budesonide has been studied in rats and mice.
The following values were determined: (See Table 1.)
Click on icon to see table/diagram/imageSubacute and chronic toxicity: After repeated oral administration of budesonide to rats (in doses comparable to those used in man), reduced numbers of leucocytes (especially lymphocytes) and regression of the thymus gland were observed. There were also signs of atrophy-induced adrenal inactivity. Increased milk duct proliferation and secretory activity were found in the mammary glands. In a long-term study (104 weeks) in female rats, haematocrit, haemoglobin and erythrocytes were reduced. In the same dose groups, neutrophil counts tended to be increased and lymphocytes, eosinophils and normocytes decreased. Only in male rats were the number of lymphocytes significantly reduced (immunosuppressant effect) and alkaline phosphatase slightly increased.
In dogs, packed cell volume was reduced and concentrations of alkaline phosphatase and alanine aminotransferase increased. Atrophy of the adrenal cortex and lymphatic system, increased myocardial content and elevated hepatic glycogen content (hepatomegaly) were also demonstrated.
Mutagenic potential: Budesonide had no mutagenic effects in a series of in vitro and in vivo tests.
Carcinogenic potential: A slightly increased number of basophilic hepatic foci were observed in male rats treated with budesonide for up to 104 weeks compared to control animals. In carcinogenicity studies, the incidence of primary hepatocellular neoplasms (0.025 and 0.05 mg/kg/day), astrocytomas (male rats, 0.05 mg/kg/day) and mammary tumours (female rats, 0.05 mg/kg/day) was significantly increased. The hepatic tumours are probably due to anabolic effects and the increased metabolic burden on the liver. The results represent a class effect in which glucocorticoid receptors are probably involved.
Reproduction toxicity: Budesonide impaired fertility in rats, increased postimplantation losses and prolonged gestation. Embryotoxicity studies in rats and rabbits have produced evidence of dose-dependent embryotoxic effects (visceral and skeletal anomalies).
